Senescent cells develop a PARP-1 and nuclear factor-κB-associated secretome (PNAS)
Senescent cells develop a PARP-1 and nuclear factor-κB-associated secretome (PNAS)
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DOI：
10.1101/gad.625811
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发表时间：
2011-06-15
影响因子：
10.5
通讯作者：
Bertolotto, Corine
中科院分区：
文献类型：
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作者：
Ohanna, Mickael;Giuliano, Sandy;Bertolotto, Corine
黑色素瘤细胞可以进入衰老过程，但它们是否表达分泌表型，如其他细胞所报道的那样，尚未确定。这是至关重要的，因为这种分泌蛋白可以改变肿瘤微环境和对化疗药物的反应。更一般地说，参与衰老相关分泌组形成的分子事件尚未确定。我们在这里揭示，黑色素瘤细胞经历衰老响应于不同的刺激，包括抗黑色素瘤药物，产生炎症分泌的配置文件，其中趋化因子配体-2（CCL 2）作为一个关键的效应。因此，我们揭示了衰老诱导可能参与黑色素瘤治疗失败。我们进一步提供了衰老诱导和分泌组形成之间的分子关系，揭示了聚（ADP-核糖）聚合酶-1（PARP-1）/核因子-κ B（NF-κ B）信号级联反应，在衰老过程中激活，驱动具有促肿瘤和促转移特性的分泌组的形成。我们的研究结果还指出，在非黑色素瘤细胞中存在PARP-1和NF-κ B相关的分泌体，称为PNAS。最重要的是，PARP-1或NF-κ B的抑制阻止了分泌蛋白组的促侵袭特性。总的来说，分泌组形成中PARP-1/NF-κ B轴的鉴定为癌症的治疗干预开辟了新的途径。
Melanoma cells can enter the process of senescence, but whether they express a secretory phenotype, as reported for other cells, is undetermined. This is of paramount importance, because this secretome can alter the tumor microenvironment and the response to chemotherapeutic drugs. More generally, the molecular events involved in formation of the senescent-associated secretome have yet to be determined. We reveal here that melanoma cells experiencing senescence in response to diverse stimuli, including anti-melanoma drugs, produce an inflammatory secretory profile, where the chemokine ligand-2 (CCL2) acts as a critical effector. Thus, we reveal how senescence induction might be involved in therapeutic failure in melanoma. We further provide a molecular relationship between senescence induction and secretome formation by revealing that the poly(ADP-ribose) polymerase-1 (PARP-1)/nuclear factor-kappa B (NF-kappa B) signaling cascade, activated during senescence, drives the formation of a secretome endowed with protumoral and prometastatic properties. Our findings also point to the existence of the PARP-1 and NF-kappa B-associated secretome, termed the PNAS, in nonmelanoma cells. Most importantly, inhibition of PARP-1 or NF-kappa B prevents the proinvasive properties of the secretome. Collectively, identification of the PARP-1/NF-kappa B axis in secretome formation opens new avenues for therapeutic intervention against cancers.